Dietary intervention reverses molecular signatures of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH

We applied RNA sequencing (RNA-seq) to study the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mouse model of NASH. GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16, or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. We find that chow reversal promoted substantial benefits on metabolic, biochemical and histological outcomes accompanied by marked suppression of gene expression markers of hepatocellular senescence in GAN DIO-NASH mice. These therapeutic benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH. Overall design: RNA-seq of poly A-enriched RNA isolated from GAN DIO-NASH mice or chow-reversal sampled at 8 weeks (n = 7), 16 weeks (n = 8), and 24 weeks (n = 8). Untreated GAN DIO-NASH mice at 8 weeks (n = 9), 16 weeks (n = 8), and 24 weeks (n = 7), and chow-fed C57BL/6J mice served as controls (24 weeks, n = 8)